A Cysteine-Directed Proximity-Driven Crosslinking Method for Native Peptide Bicyclization.

Area of Science:

• Biochemistry
• Organic Chemistry
• Chemical Biology

Background:

• Efficient synthesis of modified peptides is crucial for antibody-drug conjugates and peptide libraries.
• Multicyclic peptides are attractive therapeutics, but their synthesis is challenging.
• Current methods often require specialized protecting groups or non-natural building blocks.

Purpose of the Study:

• To develop a novel, efficient, and site-specific strategy for constructing bicyclic peptides from natural peptide precursors.
• To enable the synthesis of multicyclic peptides under physiological conditions without orthogonal protecting groups.
• To demonstrate the applicability of this method for protein and phage display applications.

Main Methods:

• A cysteine-directed, proximity-driven strategy was employed for linear-to-bicycle peptide transformation.
• The method involves rapid cysteine labeling followed by amine-selective cyclization.
• The process was optimized to proceed rapidly under physiological conditions.

Main Results:

• A new method for constructing bicyclic peptides from simple natural peptide precursors was successfully developed.
• The bicyclization strategy yields peptides with specific Cys-Lys-Cys, Lys-Cys-Lys, or N-terminus-Cys-Cys stapling patterns.
• The method was validated by constructing bicyclic peptides fused to proteins and M13 phage.

Conclusions:

• The reported cysteine-directed strategy offers an efficient and versatile approach for synthesizing bicyclic peptides.
• This method overcomes limitations of conventional techniques, avoiding orthogonal protecting groups.
• The successful application in protein and phage display opens avenues for novel bicyclic peptide library construction and therapeutic development.